Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000204246
Ethics application status
Approved
Date submitted
22/01/2018
Date registered
8/02/2018
Date last updated
3/04/2019
Date data sharing statement initially provided
3/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Angiotensin-Converting Enzyme (ACE) inhibitor cessation in the setting of well-functioning Fontan hearts
Scientific title
The effect of ACE inhibitor cessation on cardiac function in the setting of well-functioning Fontan hearts
Secondary ID [1] 291683 0
Nil known
Universal Trial Number (UTN)
U1111-1195-4221
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
congenital heart defect 302848 0
Condition category
Condition code
Surgery 302330 302330 0 0
Other surgery
Cardiovascular 305496 305496 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a post-marketing, prospective, multi-centre, parellel design, open-label randomised single-blinded equivalence trial of angiotensin-converting-enzyme inhibitor (ACEI) or angiotensin II receptor blockers (ARB) cessation versus continuation in people greater than 8 years old with a Fontan circulation and preserved ventricular systolic function. The intervention group will cease their ACEI or ARB medication for 12 months. The intervention will not be personalised but adherence will be measured using a medication diary.
Intervention code [1] 300063 0
Treatment: Drugs
Intervention code [2] 300189 0
Treatment: Other
Comparator / control treatment
The control group will continue taking their current ACEI/ARB medication in the dose and frequency that they have been prescribed by their treating medical practitioner. Adherence will be measured using a medication diary.
Control group
Active

Outcomes
Primary outcome [1] 304496 0
VO2 peak within 5% range measured by cardiopulmonary exercise testing.
Timepoint [1] 304496 0
At baseline and at 12 month visits for each arm
Secondary outcome [1] 342153 0
Quality of life assessed using PedsQL, CHU-9D, EQ-5D-3L and TBQ
Timepoint [1] 342153 0
At baseline and at 12 month visits for each arm.
Secondary outcome [2] 342155 0
Hospitalisation assessed by taking medical history during clinical assessment and patient medical records
Timepoint [2] 342155 0
At baseline and at 12 month visits for each arm.
Secondary outcome [3] 342156 0
Heart failure assessed by taking medical history during clinical assessment and patient medical records
Timepoint [3] 342156 0
At baseline and at 12 month visits for each arm.
Secondary outcome [4] 342617 0
Arrhythmia assessed using ECG as part of the cardiopulmonary exercise test
Timepoint [4] 342617 0
At baseline and at 12 month visits for each arm.
Secondary outcome [5] 342618 0
Death
Timepoint [5] 342618 0
At baseline and at 12 month visits for each arm.
Secondary outcome [6] 342619 0
Blood pressure assessed with blood pressure monitor
Timepoint [6] 342619 0
At baseline and 12 month visits for each arm.
Secondary outcome [7] 342620 0
NYHA class assessed using Specific Activity Scale
Timepoint [7] 342620 0
At baseline and at 12 month visits for each arm.
Secondary outcome [8] 342621 0
Ventricular function assessed using Echocardiogram
Timepoint [8] 342621 0
At baseline and at 12 month visits for each arm.
Secondary outcome [9] 342622 0
Degree of AV valve regurgitation assessed using Echocardiogram
Timepoint [9] 342622 0
At baseline and at 12 month visits for each arm.
Secondary outcome [10] 342623 0
N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels calculated using a blood test.
Timepoint [10] 342623 0
At baseline and at 12 month visits for each arm.

Eligibility
Key inclusion criteria
1. Have a Fontan circulation
2. Are taking ACEI or ARB medication for 12 months or more.
3. Can perform a cardiopulmonary exercise test on a cycle ergometer.
Minimum age
8 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Have worse than normal ventricular function.
2. Have greater than mild atrio-ventricular or aortic valve regurgitation.
3. Have systemic hypertension.
4. Have a physical or intellectual impairment preventing exercise testing.
5. Are pregnant or intending to get pregnant during the study period or have been pregnant beyond the first trimester within 12 months prior to study recruitment..

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using computerised sequence generation and stratified by gender and age.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The assumptions made for the sample size are as follows:
o Type I error = 5%
o Power = 90%
o Equivalence margin = 5%
o Standard deviation of absolute change in peak VO2 (continuous measure with units %) = 5%
o Adjustment of 12% for drop-out

Descriptive statistics of baseline characteristics will be reported by randomised arm. For the primary outcome, two one-sided 90% confidence intervals will be used to test for equivalence.

For the secondary outcomes (measured at baseline and 12 months), if follow-up is complete for all participants, the proportion of subjects with each clinical outcome (hospitalisation, heart failure, arrhythmia and death) at 12 months (with corresponding exact 95% confidence interval) will be reported for each arm and compared using Fisher’s Exact test; otherwise the Kaplan-Meier method and the logrank test will be used if there is censoring. Summary statistics (mean, standard deviation, median, minimum, maximum) or tabulations of percentages (with exact 95% confidence intervals), will be used to describe BP (clinical outcome), NYHA class, ventricular function, degree of AV valve regurgitation, NT-proBNP and quality of life (using PedsQL, CHU-9D, EQ-5D-3L and TBQ) at each available visit for each arm. Unless stated otherwise, all statistical tests will be performed two-sided using a significance level of 5% for the secondary outcomes. If confidence intervals are to be calculated, these will be two-sided with a confidence coefficient of 95%.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2018
Actual
31/05/2018
Date of last participant enrolment
Anticipated
15/04/2019
Actual
Date of last data collection
Anticipated
15/04/2020
Actual
Sample size
Target
50
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 9838 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [2] 9840 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 9843 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [4] 9844 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 18617 0
3052 - Parkville
Recruitment postcode(s) [2] 18619 0
2145 - Westmead
Recruitment postcode(s) [3] 18623 0
2050 - Camperdown
Recruitment postcode(s) [4] 18624 0
4101 - South Brisbane
Recruitment outside Australia
Country [1] 9502 0
New Zealand
State/province [1] 9502 0
Auckland

Funding & Sponsors
Funding source category [1] 296184 0
Charities/Societies/Foundations
Name [1] 296184 0
Heart Kids Australia
Country [1] 296184 0
Australia
Primary sponsor type
Individual
Name
Prof Yves d'Udekem
Address
Cardiac Surgery
The Royal Children's Hospital
50 Flemington Road, Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 295093 0
None
Name [1] 295093 0
Address [1] 295093 0
Country [1] 295093 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297427 0
The Royal Children's Hospital HREC
Ethics committee address [1] 297427 0
50 Flemington Rd, Parkville VIC 3052
Ethics committee country [1] 297427 0
Australia
Date submitted for ethics approval [1] 297427 0
05/05/2017
Approval date [1] 297427 0
21/11/2017
Ethics approval number [1] 297427 0
HREC/17/RCHM/79

Summary
Brief summary
This study will look at the impact of angiotensin receptor inhibitors (ACEI) cessation in children and adults with a Fontan circulation and normal heart contraction. Many children born with a single cardiac pumping chamber undergo a Fontan operation. Due to concerns about potential late heart failure, many are prescribed ACEI although they have good heart function, possibly exposing them to unnecessary risk of adverse drug reactions and the burden of lifelong medication. Evidence has shown ACEI are of benefit in a failing 2-ventricle heart, but there is no literature to suggest they are of benefit in the Fontan circulation.

This project aims to demonstrate that cessation of ACEI, or closely related angiotensin receptor blockers (ARB), is safe and non-inferior to ACEI/ARB continuation in children and adults with a Fontan circulation with good cardiac systolic function and without other indications for continuation such as moderate or greater valvar regurgitation and/or hypertension.
We hypothesise that:
1. Cessation of ACEI or ARB does not result in a significant decline in peak exercise capacity or cardiac function over a 12-month follow-up period.
2. Cessation of ACEI or ARB results in improved quality of life and reduced medical expenses over 12 months.

If the hypotheses hold true it will dispel a historical concern that will relieve a large number of Fontan patients and their families of an unnecessary burden, improving quality of life and sense of well-being. It will improve the futures and the lives of people affected by childhood heart disease. Lifelong medication carries with it an important psychological burden because of the effects on one’s sense of well-being and “normalness”. This can be especially burdensome for children and their families. Medications also impose a risk of adverse reactions, and may also be costly, for example an adult on a standard dose of ACEI without a Healthcare Card could expect to pay $265 per year. Although, in this current era, we strive for evidence-based medical practice, there is little evidence to guide us in many areas of congenital heart medicine. Some practices, that have been routine for many years, may actually be useless or even cause harm. The implementation of ACEI as a routine for people with the unique single-ventricle Fontan circulation is practiced in many centres, although there is virtually no evidence to support their use.

Future implications of this trial would include reduced morbidity related to unnecessary medication administration, insight into the disease processes that may or may not contribute to late Fontan failure, a better understanding of the consequences of ACEI use including the social and psychological impact, improved quality of life, and streamlined and improved management strategies for people living with a Fontan heart.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74002 0
Prof Yves d'Udekem
Address 74002 0
Cardiac Surgery Department
The Royal Children's Hospital
50 Flemington Road, Parkville VIC 3052
Country 74002 0
Australia
Phone 74002 0
+61 3 93455203
Fax 74002 0
Email 74002 0
[email protected]
Contact person for public queries
Name 74003 0
Yves d'Udekem
Address 74003 0
Cardiac Surgery Department The Royal Children's Hospital 50 Flemington Road, Parkville VIC 3052
Country 74003 0
Australia
Phone 74003 0
+61 3 93455203
Fax 74003 0
Email 74003 0
[email protected]
Contact person for scientific queries
Name 74004 0
Yves d'Udekem
Address 74004 0
Cardiac Surgery Department
The Royal Children's Hospital
50 Flemington Road, Parkville VIC 3052
Country 74004 0
Australia
Phone 74004 0
+61 3 93455203
Fax 74004 0
Email 74004 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Only the results from the test will be forwarded to the respective cardiologist to be kept on file. If results fall outside what is considered the 'normal range' for patients with a Fontan circulation these will be fed back to the patients treating cardiologist and the patients.
When will data be available (start and end dates)?
Start: 24/05/2018 End: 01/04/2020
Available to whom?
The results from the test will be available to the treating cardiologist
Available for what types of analyses?
Data will be available for analysis at the discretion of the coordinating principal investigator.
How or where can data be obtained?
The results from the test will first be entered onto a password secure website. They will then be sent to each treating cardiologist.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.